JPH045277A - 4,5,6,7-tetrahydrobenzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is H or lower alkoxy; A is O, S, N, CH=N, etc.) and a salt thereof. EXAMPLE:2-(4,5,6,7-Tetrahydro-5-benzimidazolyl)-3,4-dihydroquinazoline. USE:An antiemetic drug suppressing vomiting caused by carcinostatic agent such as cisplatin and by radiation. PREPARATION:According to the reaction formula, an aniline derivative shown by formula II is reacted with 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid shown by formula III or a reactive derivative thereof to given compound shown by formula I. The reaction is usually carried out in a solvent (e.g. acetone, dioxane or ether) at room temperature or under heating.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to 4.5.6.7-titrahydropenzimidazole derivatives and salts thereof useful as pharmaceuticals.

The compound of the present invention is a novel compound having 5-HT3 antagonistic activity.

(Background of the invention) Conventionally, as a 5-HT3 antagonist, JP-A-59-366
Azabicyclo compounds described in JP-A No. 75, JP-A-59-67284, tetrahydrocarbazole derivatives described in JP-A-60-214784, JP-A-61-Sho.
Azabicyclo compounds described in Japanese Patent No. 275276 are known.

(Solution Means) The present inventors have created nine various new compounds for the purpose of searching for compounds having excellent 5-HT3 antagonistic activity, and have proceeded with their screening, and found that the following general formula (I
We have found that 4, 5.6.7) 7-hydrobenzimidazol derivatives shown in ) have excellent 5-HT3 antagonistic activity.

The present invention has now been completed.

That is, the present invention is based on the general formula (I) (wherein R1 represents a hydrogen atom or a lower alkoxy group, A
is O, S, N, CH2-N ((However, R2 means a hydrogen atom or a lower alkyl group) or CH=N
means base. ) The present invention relates to a 4,5,6,7-titrahydrobenzimidazole derivative or a salt thereof.

In the definition of the group in the general formula herein, "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Therefore, "lower alkyl groups" include methyl, ethyl, propyl, butyl, pentyl, hexyl,
Examples include inpropyl group, isobutyl group, tert-butyl group, impentyl group, tert-pentyl group, inhexyl group, and the like.

"Lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, infropoxy group, imbutoxy group,
tert-butoxy group, isopentyloxy group,
tert-pentyloxy group.

Examples include isohexyl oxyne group and 2-ethylbutoxy group.

The compounds of the present invention can also form salts. Such salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, boric acid, phosphoric acid, sulfuric acid, as well as acetic acid, tartaric acid, maleic acid, fumaric acid.

Examples include salts with organic acids such as citric acid, succinic acid, benzoic acid, and p-toluenesulfonic acid.

Furthermore, two of the compounds of the present invention have a tetrahydroimidazole skeleton and an asymmetric carbon atom in the molecule,
The compound included in the general formula (I) has isomers such as tautomers and optical isomers based on asymmetric carbon atoms.

The present invention includes isolated or mixtures of these isomers.

The method for producing the compound of the present invention will be specifically explained below.

Production method 1゜ (In the formula, A and R1 represent the same meanings as above.) The compound (I) of the present invention is an aniline derivative represented by the general formula (I[), and 4,5.6 represented by the formula (III). It can be obtained by reacting 7-tetrahydrobenzimidazole-5-carboxylic acid or a reactive derivative thereof.

The reaction between compound (n) and compound (III) or its reactive derivative is usually carried out in a solvent at room temperature to elevated temperature.

The solvent is not particularly limited as long as it does not participate in the reaction.

Commonly used ones include acetone, dioxane,
ether, tetrahydrofuran, methyl ethyl ketone,
Chloroform, dichloroethane, dichloromethane, ethyl acetate, ethyl formate, dimethylformamide.

Examples include dimethyl sulfoxide. These solvents may be mixed and used as appropriate.

Compound (m) is used in the form of a free carboxylic acid or is subjected to a reaction as a reactive derivative of a carboxylic acid. Reactive derivatives of carboxylic acids include active esters (such as benzotriazole esters), mixed acid anhydrides,
Acid halides, activated amides, acid anhydrides, acid azides, etc. are used.

When compound (III) is used in the form of free carboxylic acid, N,N'-dicyclohexylcarbodiimide,
After condensation with a condensing agent such as N,N'-diethylcarbodiimide, if necessary, use a dehydrating agent such as sulfuric acid or polyphosphoric acid, or directly use a dehydrating agent such as sulfuric acid or polyphosphoric acid. preferable.

Depending on the type of reactive derivative of carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the two reactions to proceed smoothly. Such bases include inorganic bases such as sodium hydrogen carbonate+7um, carrum hydrogen carbonate, sodium carbonate, potassium carbonate, trimethylamine,
Examples include organic bases such as triethylamine, dimethylaniline, and pyridine.

Production method (n) This production method is a method for producing a compound represented by general formula (Ib) (a compound in which A means a CH═N group in the compound of general formula (I)). Compound (Ib) is a compound (
JV) can be produced by oxidizing it.

Oxidation of compound (IV) can be carried out by two conventional methods. For example by oxidizing agents such as lead tetraacetate, manganese dioxide; by metals such as sulfur, selenium; or by catalytic oxidation. The catalytic oxidation (dehydrogenation) agent is usually palladium.

Catalysts such as platinum and rhodium can be used.

This reaction typically involves, for example, water, alcohols (eg methanol, ethanol, etc.), decalin, benzene, etc. or mixtures thereof.

It should be carried out in a solvent that does not adversely affect the reaction.
Alternatively, it can be carried out without a solvent.

The reaction temperature is not critical, and the reaction is usually carried out under heat.

The compound of the present invention thus produced is isolated and purified in its free form or as a salt thereof. Isolation and purification include extraction, crystallization, and recrystallization.

This is carried out by applying ordinary chemical operations such as various chromatography.

Racemic compounds can also be obtained by using appropriate raw materials or by general racemic resolution methods [for example, a method of optically resolving a diastereomer salt with a general optically active acid (tartaric acid, etc.)] can lead to stereochemically pure isomers.

(Effect of the invention) The compound of the present invention or a salt thereof specifically inhibited serotonin-induced transient bradycardia in anesthetized rats.
It was confirmed that it has HT3 antagonistic effect. Therefore, the compounds of the present invention suppress vomiting caused by anticancer drugs such as cisplatin and radiation, and are useful for the prevention and treatment of migraines, compound headaches, trigeminal neuralgia, anxiety symptoms, gastrointestinal motility disorders, peptic ulcers, irritable bowel syndrome, etc. It is believed that there is.

The pharmacological effects of the compounds of the present invention were confirmed in the following manner.

1) 5-) IT3 receptor antagonism Nine-week-old male Wistar rats were anesthetized by intraperitoneal administration of urethane at 1 g/kg, and blood pressure and heart rate during 9 artificial breaths were measured. The transient decrease in heart rate and blood pressure caused by intravenous administration of serotonin or 2-methylserotonin, a selective 5-HT3 agonist, was used as an indicator of a response mediated by 5-HT3 receptors. (Bezold-Jarish reflex; Palintal A, S, Physiol,
Rev. +53+159+1973).

The compound of the present invention or a salt thereof is administered intravenously 10 minutes before administration of serotonin and 2-methylserotonin (0.03-
3μg/kg) or oral administration 60 minutes before
30 μg/kg).

Administration of serotonin and 2-methylserotonin inhibited the decrease in heart rate and blood pressure in a dose-dependent manner.

2) Anticancer drug-induced emesis suppressive effect Subcutaneous or oral administration of 001 to 0.3111 g/kg of the 9 compounds of the present invention to male phelenots weighing 1 to 1.5 kg suppresses the emesis induced by intraperitoneal administration of cisplatin 10 μ/kg. was suppressed.

3) Effect on suppressing stressed fecal excretion Nine-week-old male Wistar rats were housed in cages for stress stress, and the number of feces excreted was measured.

The compound of the present invention or a salt thereof can be administered intravenously (1 to 100μ
g/kg) inhibited the phototransmission of fecal excretion caused by hugging stress in a dose-dependent manner.

(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.

Example 1 ・H2SO.

0-Aminobenzylamine (o2sg) was pretreated with 4,5,6.7-titrahydropenzimidazole-5.
- Carboxylic acid/sulfate (o, s3g) and thionyl chloride (
Add it little by little at room temperature to a dimethylformamide (5mt) solution of acid chloride prepared from 2mZ).

Stir overnight. Water was added to the reaction solution, the pH was adjusted to 8 with IN sodium hydroxide, and the solvent was concentrated under reduced pressure.

The operation of filtering the ethanol-soluble portion of the residue and concentrating the solvent was repeated twice, and the obtained crystals were recrystallized from methanol-dichloromethane to form 2-(4,5,6°7-tetrahydro-5-benz). 0.41 g (81%) of imidazolyl-3,4-dihydroquinazoline was obtained.

・Melting point 210-214℃ (dec,) ・NMR (DM
SO-a6) δ: 1.57-2.23 (2H, m), 2.23-
2.85 (5H, m).

3.38 (LH, br), 4.47 (2H, s),
6.65-7.24 (5H, m), 7.39 (IH,
s) #MS: rn/z 252 (M+) Example
2 The following compound was obtained in the same manner as in Example 1.

1-Methyl-2-(4,5,6,7-titrahydropenzimidazol-5-yl)benzimidazole bone 1,
57 malate salt melting point 209-211℃ (MeOH-CH3CN)
・Elemental analysis value (Cl5H16N4・1.5 C4H40
4.0. (as lH2O) C (%) H (%)
N (%) Calculated value 58.90 5.23 13.
08 experimental value 58.68 5.30 13.38
4 MS: m/z 252 (M+, as a free unit) Example 3 5-(4-methoxy-2-penzimita "zolyl)-4"
,5,6,7-titrahydrobenzimidazole 05
Fumarate, melting point 193-195°C (MeOHCH3CN)
・Elemental analysis value (Cl5H111N40・0.5c4H4
o4・1.5rH20) C (%) H (%)
N (%) Calculated value 57.78 5.99
15.85 Experimental value 57,87 5.69 15
．． 69・MS: m/s 268 (M", as a free unit) Example 4 Purified by silica gel column chromatography using a chloride-methanol mixed solvent and treated with hydrochloric acid in ethyl acetate, showing a melting point of 277-280°C , 2-
0.6 g of (4,5,6,7-titrahydropenzimidazol-5-yl)benzoxazole hydrochloride was obtained.

・Elemental analysis value (as cl4 H14N30CI) C(
%) H (%) N (%) cl (%) Calculated value 60.9
8 5.12 15.24 12.86 Experimental value 60.
74 5.03 15.16 12.97 Mass spectrum (El): m/z 239 (M+, as 7-li base) 4.5,6.7-titrahydrobenzimidan-5-carboxylic acid 1. 32 g and 0.6 g of orthoaminophenol in polyphosphoric acid SmZ, 170-
It was treated at 180°C for 1 hour. 100 ml of ice water was added to the reaction solution, the mixture was made alkaline with potassium carbonate, and then extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was converted into methylene chloride Example.
5 The following compound was obtained in the same manner as in Example 4.

2-(4,5,6,7-titrahydropenzimitazol-5-yl)benzothiazole hydrochloride, melting point 26
5-268℃ (decomposition) Nuclear magnetic resonance spectrum (DMSO-d6) 'δ: 2
．． 00-3.80 (7H, m), 7.30-8.20
(4H, m).

8.97 (I H,s) Mass spectrum (EI): m/s 255 (M
+, as free pace) elemental analysis value (Cl5H14N
4・C,1 (as 40) C (%) H (%)
N (%) Calculated value 62,29 4.95 1
5.29 Experimental value 62.02 4.88 15.2
5M5: m/z 250 (M+, as a free integral) Example 6 2- (4,5,6,7-tetrahydro-5-penzimitazolyl) -3,4-dihydroquinazoline (0,
A mixture of 5% palladium-carbon (0.45 g) and 5% palladium-carbon (0.45 g) in methanol (15+nl) was heated under reflux overnight. The reaction solution was passed through f and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (1 sg). Elute with 10% methanol-chloroform, 2-(4,5,6,
7-tetrahydro-5-benzimidazolyl) quinazoline was obtained in an amount of 18%, which was used as the fumarate salt.

・Melting point 188-189℃ (Me OH-CH3CN
) Patent applicant Yamanouchi Pharmaceutical Co., Ltd. Agent Patent attorney Shozo Nagai

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a lower alkoxy group,
There are O, S, N, ▲mathematical formulas, chemical formulas, tables, etc.▼(
(However, R^2 means a hydrogen atom or a lower alkyl group)) or means a CH=N group. ) A 4,5,6,7-tetrahydrobenzimidazole derivative or a salt thereof.